Delivery of a therapeutic agent from an endolumenal medical device can be desirable for a variety of applications. Therapeutic agents can be released from a medical device, such as an expandable stent or valve, to treat or mitigate undesirable conditions including restenosis, tumor formation or thrombosis. Procedures for mitigating certain conditions can include implantation of a device comprising a therapeutic agent. For example, the implantation of stents during angioplasty procedures has substantially advanced the treatment of occluded body vessels. Angioplasty procedures such as Percutaneous Transluminal Coronary Angioplasty (PTCA) can widen a narrowing or occlusion of a blood vessel by dilation with a balloon. Occasionally, angioplasty may be followed by an abrupt closure of the vessel or by a more gradual closure of the vessel, commonly known as restenosis. Acute closure may result from an elastic rebound of the vessel wall and/or by the deposition of blood platelets and fibrin along a damaged length of the newly opened blood vessel. In addition, restenosis may result from the natural healing reaction to the injury to the vessel wall (known as intimal hyperplasia), which can involve the migration and proliferation of medial smooth muscle cells that continues until the vessel is again occluded. To prevent such vessel occlusion, stents have been implanted within a body vessel. However, restenosis may still occur over the length of the stent and/or past the ends of the stent where the inward forces of the stenosis are unopposed. To reduce this problem, one or more therapeutic agents may be administered to the patient. For example, a therapeutic agent may be administered systemically, locally administered through a catheter positioned within the body vessel near the stent, or coated on the stent itself.
A medical device can be coated with a therapeutic agent in a manner suitable to expose tissue near the implantation site of the medical device to the therapeutic agent over a desired time interval, such as by releasing the therapeutic agent from an implanted stent into surrounding tissue inside a body vessel. Various approaches can be used to control the rate and dose of release of therapeutic agents from an endolumenal medical device. The design configuration of an implantable device can be adapted to influence the release of therapeutic from the device. A therapeutic agent can be included in the endolumenal medical device in various configurations. In some devices, the therapeutic agent is contained within an implantable frame or within a coating on the surface of the implantable frame. An implantable frame coating can include a bioabsorbable material mixed with a therapeutic agent, or coated over the therapeutic agent. Some endolumenal medical devices comprise an implantable frame with a porous biostable material mixed with or coated over a therapeutic agent. Endolumenal medical devices can also comprise a biostable material containing a dissolvable material and a therapeutic agent, where dissolution of the removable material upon implantation forms pores that release the therapeutic agent.
The design of a controlled release medical device can also depend on the desired mode of implantation of the device. The device can be adapted to the appropriate biological environment in which it is used. For example, a coated medical device for percutaneous transcatheter implantation can be sized and configured for implantation from the distal portion of a catheter, and adapted for expansion at the point of treatment within the body vessel by balloon or self-expansion. An endolumenal medical device can also be adapted to withstand a desired amount of flexion or impact, and should provide delivery of a therapeutic agent with a desired elution rate for a desired period of time.
Paclitaxel, and taxane analogues and derivatives thereof, can be used as a therapeutic agent coated on and released from implantable devices, such as stents, to mitigate or prevent restenosis. Paclitaxel is believed to disrupt mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles (i.e., a microtubule stabilizing agent).
Taxane therapeutic agent molecules having the same molecular structure may be arranged in different solid forms. Taxane therapeutic agent molecules can exist in solvated or non-solvated solid forms that can be characterized and differentiated by one or more physical properties, including the rate of dissolution in various elution media (e.g., cyclodextrin or porcine serum) prior to implantation. Typically, taxane therapeutic agents in a solvated solid form dissolve more slowly in blood than non-solvated solid forms, but are less durable than the non-solvated solid forms. Once dissolved, the taxane therapeutic agent molecules having identical molecular structures but originating from different solid forms are indistinguishable in solution. Solid forms of paclitaxel at room temperature include: amorphous paclitaxel (“aPTX”), dihydrate crystalline paclitaxel (“dPTX”) and anhydrous crystalline paclitaxel. These different solid forms of paclitaxel can be characterized and identified using various solid-state analytical tools, for example as described by Jeong Hoon Lee et al., “Preparation and Characterization of Solvent Induced Dihydrate, Anhydrous and Amorphous Paclitaxel,” Bull. Korean Chem. Soc. v. 22, no. 8, pp. 925-928 (2001), incorporated herein by reference in its entirety. For example, amorphous and dihydrate taxane solid forms may be readily identified and differentiated by visual appearance and elution rates. The dihydrate taxane solid form typically has an opaque white color, while the amorphous dihydrate taxane solid form typically has a clear transparent appearance. In addition, the presence of different solid forms of the taxane therapeutic agent in a medical device coating can be identified and quantified by contacting the coating with an elution medium that selectively dissolves one solid form more readily than a second solid form. In solution with an elution medium, such as porcine serum or blood, the presence of the taxane therapeutic agent can be identified, for example by using ultraviolet (UV) spectroscopy or high pressure liquid chromatography (HPLC). In certain elution media such as porcine serum, the solvated taxane therapeutic agent structures dissolve more slowly than the non-solvated solid forms. Non-solvated solid forms include amorphous or anhydrous solid forms.
U.S. Pat. No. 6,858,644, filed Nov. 26, 2002 by Benigni et al. (“Benigni”), teaches a crystalline solvate comprising paclitaxel and a solvent selected from the group consisting of dimethylsulfoxide, N,N′-dimethylformamide, N,N′-dimethylacetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone, and acetonitrile and combinations thereof. However, Benigni does not describe implantable device coatings comprising crystalline paclitaxel forms with different elution rates. Benigni discloses various solid forms of paclitaxel, including a first solid form reported as a highly water insoluble crystalline, granular, solvent-free form. The first solid form is substantially non-hygroscopic under normal laboratory conditions (relative humidity (RH) approximately 50-60%; 20-30° C.). However, when contacted with an atmosphere having a relative humidity greater than about 90%, or in aqueous suspensions, dispersions or emulsions, the first paclitaxel solid form reportedly converts (as a function of time, temperature, agitation, etc.) to a thermodynamically more stable second solid form. The second solid form is described as a trihydrate orthorhombic form having six water sites per two independent paclitaxel molecules (one paclitaxel “dimer”). These hydrated crystals reportedly present a fine, hair-like appearance and are even less water soluble than the first solid form. The second solid form is reportedly formed in aqueous suspensions or through crystallization from aqueous solvents in the presence of a large excess of water. This form is also disclosed in patent application EP 0 717 041, which describes the second solid form as being characterized by single crystal X-ray diffraction studies as being orthorhombic, with unit cells containing two crystallographically independent molecules of paclitaxel associated with hydrogen bonds to form a “dimer”. Mastropaolo, et al. disclosed a crystalline solvate of paclitaxel obtained by evaporation of solvent from a solution of Taxol® in dioxane, water and xylene. Proc. Natl. Acad. Sci. USA 92, 6920-24 (July, 1995). This solvate is indicated as being unstable, and, in any event, has not been shown to effect purification of crude paclitaxel. The thin plate-like crystals are reported to contain five water molecules and three dioxane molecules per two molecules of paclitaxel. None of these references describe a durable taxane coating having an elution profile that can be altered by treatment of a medical device coating to vary the solid form composition of the coating.
There remains a need for intravascularly-implantable endolumenal medical devices comprising a coating of a releasable therapeutic agent having sufficient durability to resist the undesirable premature release of the therapeutic agent from the device prior to implantation at a point of treatment within a body vessel. For example, a coating comprising a releasable therapeutic agent is typically applied to an endolumenal medical device prior to crimping the medical device onto a delivery catheter. Coatings desirably have sufficient durability to withstand the crimping process with minimal loss of a therapeutic agent. Many medical device coatings adapted for controlled release of taxane therapeutic agent such as paclitaxel rely on a polymer that is applied in combination with the releasable therapeutic agent to both controls the release of the therapeutic agent from the medical device surface and to impart desired mechanical durability to the coating. For example, published U.S. patent application Ser. No. 10/213,126 (filed Aug. 5, 2002 and later published as US2004/0024448) discloses a stent coating comprising a releasable therapeutic agent combined with a fluoropolymer elastomeric to provide desirable mechanical properties such as good flexibility and durability. Similarly, U.S. patent application Ser. No. 10/662,877 (filed Sep. 16, 2004, and later published as US2004/0117007) discloses incorporation of polymers in a stent coating to “impart desirable properties of adhesion, cohesion, durability, and flexibility.” Alternatively, medical device coatings comprising a dihydrate solvated taxane therapeutic agent such as dihydrate paclitaxel (paclitaxel-2H2O) may provide a desired sustained release of paclitaxel in the absence of a polymer coating, but may lack a desired level of durability (See, e.g., Jeong Hoon Lee et al., “Preparation and Characterization of Solvent Induced Dihydrated, Anhydrous and Amorphous Paclitaxel,” Bull. Korean Chem. Soc. v. 22, no. 8, pp. 925-928 (2001)). Other solid forms of taxane therapeutic agents, such as the amorphous solid form, provide more durable coatings but often provide for an undesirably rapid release of the taxane therapeutic agent upon implantation for certain applications.
In addition, existing packaging systems may not provide adequate protection of coatings of taxane therapeutic agents. Packaging systems for medical devices with taxane therapeutic agents may include a thermoform tray insert in a foil pouch, or a thermoform tray having a Tyvek® lid in a foil pouch, into which the coated medical device is vacuum sealed. Such conventional packaging for coated medical devices do not provide for regulation of ambient conditions such as circulation of air or exposure to light and oxygen. Without such appropriate regulation, the efficacy of the therapeutic agent coating maybe reduced.
What are needed are methods for treating medical device coatings that decrease the rate of post-implantation release of a taxane therapeutic agent without compromising a desired level of coating durability. For example, methods are needed to convert a highly durable but rapidly-eluting taxane therapeutic agent medical device coating to a less durable but slower-eluting taxane therapeutic medical device coating prior to implantation of the coated medical device in a patient. Such methods would permit the sale and transport of the highly durable medical device coating without undesirably compromising the physical quality of the coating, followed by the implantation of a medical device coating with a desirably longer period of elution within a body vessel. Without such methods, a trade-off exists between selecting coatings with a desired durability for packaging and transport, and desirably sustained elution of the taxane therapeutic agent upon implantation.
There is also a need for a medical device with a coating of a releasable therapeutic agent coating having sufficient durability to resist the undesirable premature release of the therapeutic agent from the device prior to implantation at a point of treatment within a body vessel.
Also needed are coating methods that provide a controlled release of a taxane therapeutic agent without requiring a polymer to provide a desired release rate. Preferably, an implanted medical device releases a therapeutic agent at the site of medical intervention to promote a therapeutically desirable outcome, such as mitigation of restenosis.
In addition, there is a need for sufficiently durable medical device coatings comprising or consisting of a sustained-release taxane therapeutic agent while being free from contact with non-biocompatible organic solvents.
Packaging adapted to maintain a taxane therapeutic agent is also needed. For example, packages adapted to provide a chamber in which a taxane therapeutic agent can be treated to decrease the elution rate of the coating are also needed.
In particular, there remains a need for intravascularly-implantable medical devices capable of releasing a taxane therapeutic agent at a desired rate and over a desired time period upon implantation, where the rate of release may be altered by treatment of the coating after deposition and preferably prior to implantation.